A Novel Diagnostic and Prognostic Biomarker Panel for Endothelial Cell Damage–Related Complications in Allogeneic Transplantation

Abstract

Noninfectious transplantation-related complications (TRCs), such as graft-versus-host disease or TRC with endothelial cell damage (TRC-EC), remain as the major obstacle for successful allogeneic hematopoietic cell transplantation (allo-HCT). However, the diagnosis and prognosis for the emergence of these complications are difficult to define during the early post allo-HCT period. Here, we tried to generate a novel diagnostic system for TRC-EC by analyzing 188 adult patients who received allo-HCT. Our study found that the peripheral blood levels of angiopoietin 2 (ANG2), C-reactive protein (CRP), D-dimer, and thrombomodulin (TM) at the onset of TRCs were significantly associated with the development of TRC-EC. We next developed a composite biomarker panel incorporating the risk values of ANG2, CRP, D-dimer, and TM at the onset of TRCs, which classified these patients into 3 risk groups: low, intermediate, and high risk. As a result, the panel was useful not only for the diagnosis of TRC-EC with high specificity and sensitivity, but also for the prediction of the patients' long-term outcome. The 5-year overall survival (OS) rates of patients in the low-, intermediate-, and high-risk groups since the occurrence from TRCs were 76.2%, 54.9%, and 26.9%, respectively, and the high-risk score was significantly associated with both poor OS (hazard ratio [HR], 5.60; 95% confidence interval [CI], 2.81 to 11.20; P < .01) and frequent nonrelapse mortality (HR, 19.75; 95% CI, 5.59 to 69.77; P < .01). Thus, the composite panel proposed in this study provides a powerful tool for the diagnosis of TRC-EC and for the prediction of survival for patients with TRC-EC after allo-HCT.

Endothelial damage is aggravated in acute GvHD and could predict its development

“…[44][45][46][47] These findings provide a new understanding of the pathophysiology of aGvHD, as they indicate that there is an enhanced endothelial vulnerability even before the aGvHD debut. 48 The results are in agreement with previous observations correlating aGvHD and chronic GvHD with high VWF levels in plasma. 26,27 The present study goes an step further demonstrating that VWF levels are elevated even earlier than the onset.…”

Higher Peak Tacrolimus Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation Increase the Risk of Endothelial Cell Damage Complications

“…We analyzed the impact of these variables and found that grades II to IV acute GVHD was another risk factor for TRC-EC but disease status, conditioning regimen, donor type, and donor source were not. Similar to previous reports [1,2]. the concurrence of TRC-EC with acute GVHD was also seen in the present study.…”

“…As previously reported, TRC-EC is defined as noninfectious TRCs with endothelial cell damage, including SOS, TAM, intestinal TAM (i-TAM), capillary leak syndrome, IPS, and diffuse alveolar hemorrhage after allo-HSCT [1,2]. We diagnosed TRC-EC at its initial presentation during the post-transplantation clinical course.…”

“…The development of TRC-EC was associated with poor OS. Tatekawa et al [1] previously developed a composite biomarker panel for TRC-EC, including angiopoietin 2, C-reactive protein, D-dimer, and thrombomodulin. The panel is diagnostically useful for distinguishing TRC-EC from acute GVHD as well as for the prognosis of outcomes.…”

Donor Heme Oxygenase-1 Promoter Gene Polymorphism Predicts Survival after Unrelated Bone Marrow Transplantation for High-Risk Patients

“…One major limitation of this study is the lack of results that conclude the functional roles of the HO-1 SNP in survival outcomes after BMT. The association of the surrogate markers for endothelial cell damage after allo-HSCT, such as serum levels of angiopoietin 2 and thrombomodulin [44], with the HO-1 SNP may offer useful information on this issue. Unfortunately, no serum samples were available in the present study.…”